Comparing Fourteen Consensus Biomarkers of Aging: Epigenetic Pace of Aging as the Strongest Predictor of Mortality in BASE-II

Abstract In many countries, lifespan has been increasing faster than healthspan(definition), leading to more years spent with late-life disease and highlighting the need for reliable biomarkers to measure biological aging and to plan personalized interventions to extend healthspan. We used data from the Berlin Aging Study II (BASE-II, 60-80 years of age at baseline, average follow-up 7.4±1.5 years, range 3.9-10.4, n=1,083) to compare 14 biomarkers of aging recently consented by an expert panel for the use as outcome measures in intervention studies: Insulin-like growth factor 1 (IGF-1), growth-differentiating factor-15 (DNA methylation derived, DNAmGDF15), high sensitivity C-reactive protein (CRP), interleukin-6 (IL 6), muscle mass, muscle strength, hand grip strength (HGS), Timed-Up-and-Go (TUG), gait speed, standing balance test, frailty index (FI), cognitive health, blood pressure, and epigenetic age (DunedinPACE). Cox proportional hazard regression analyses were performed to investigate the predictive role for all-cause mortality and to identify subgroups of the three most frequent causes of death observed in BASE-II. Results were adjusted for age, sex, lifestyle factors, and genetic ancestry. In adjusted models of all-cause mortality, HGS, IL 6, standing balance, cognitive health, and epigenetic age (DunedinPACE) significantly predicted mortality, with the epigenetic age (DunedinPACE) emerging as the strongest predictor. In contrast, CRP, Gait Speed, IGF-1, blood pressure, muscle mass, DNAmGDF15, FI and TUG were not associated with mortality. These results were corroborated in subgroup analyses stratified by cause of death. Feature selection identified a minimal biomarker set comprising muscle mass, standing balance, and epigenetic age (DunedinPACE) that predicted mortality with nearly the same discriminative accuracy (C-index = 0.63) as the full model including all biomarkers (C-index = 0.65).